Macitentan is an endothelin receptor antagonist (ERA) and is chemically known as N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide and represented by the following structural formula (I);

Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. Macitentan was approved by US FDA on Oct. 13, 2013 for the treatment of pulmonary arterial hypertension (PAH) and commercially available under the brand name of Opsumit.
Macitentan and process for its general preparation method was disclosed in U.S. Pat. No. 7,094,781. The process for the preparation of macitentan was first exemplified in Journal of Medicinal Chemistry 55, 7849-7861, 2012 and the disclosed process is schematically represented as below:

The above disclosed process has the following disadvantages;                Step b) and step g) involves the use of sodium hydride. In general, sodium hydride is highly flammable and can ignite in air especially upon contact with moisture. Need to carry out sodium hydride reactions under inert atmosphere such as nitrogen or argon gas. The use of sodium hydride in commercial scale is not advisable in safety point of view;        The conversion of compound IV to compound Va in step d) involves the use of highly corrosive phosphoryl chloride under neat conditions at a temperature of about 130° C. and distillation of the highly corrosive phosphoryl chloride after completion of the reaction;        Macitentan obtained by the above process having higher amount un-reacted compound VII as an impurity, which is not easy to remove even after repeated purifications.        
IPCOM000236886D journal publication discloses the preparation of amorphous macitentan by the reaction of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl)-N′-propyl-sulfamide with 5-bromo-2-chloropyrimidine in presence of lithium amide in tetrahydrofuran and dimethylformamide. Further WO2016009322 and 3341/MUM/2014 also discloses amorphous form of macitentan and process for its preparation.
WO2014198178 publication discloses crystalline Form II of macitentan as well as methanol, nitromethane and methyl tert-butyl ether solvates of macitentan, process for their preparation and pharmaceutical composition comprising the same. Further this publication designates the crystalline form of macitentan obtained from methanol crystallization as per Journal of Medicinal Chemistry 55, 7849-7861, 2012 as “Form I”.
CN105461637A publication discloses crystalline form of macitentan and process for its preparation. The disclosed process involves crystallization of crude macitentan from a solvent selected from methanol, ethanol, isopropanol, diethyl ether, acetonitrile, acetone, methylene chloride, ethyl acetate, n-hexane, n-heptane, petroleum ether or mixture thereof.
CN105461638A publication discloses crystalline Form H of macitentan and process for its preparation. The disclosed process involves crystallization of crude macitentan from ethyl acetate solvent or its mixture with methanol or n-hexane.
CN105622523A publication discloses crystalline form of macitentan and process for its preparation. The disclosed process involves dissolution of macitentan in methylene chloride, subjecting to carbon treatment, filtering and washing the filter cake with hot methanol; concentrating the filtrate up to 0.05-0.5 g/ml; followed by adding methylisobutyl ketone to the concentrate, cooling to room temperature and filtering the crystalline macitentan.
CN105461639A publication discloses a process for purification of macitentan, which involves crystallization of crude macitentan from ethyl acetate or its mixture with methanol or hexane.
CN103819411 publication discloses the preparation of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N′-propyl sulfonamide, which involves the reaction of 5-(4-bromophenyl)-4,6-dichloropyrimidine with N-propylsulfamoyl amide in presence of alkoxy metal compound.
WO2014155304 publication discloses the preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidine-4-yl)propane-1-sulfamide and the disclosed process represented schematically as follows:

WO2015004265 publication discloses process for the preparation of N-(5-(4-bromo phenyl)-6-(2-hydroxyethoxy) pyrimidine-4-yl)propane-1-sulfamide. The disclosed process involves the reaction of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)-propane-1-sulfamide with ethylene glycol in presence of potassium tertiary butoxide and extracting the obtained N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy) pyrimidine-4-yl)propane-1-sulfamide with MIBK.
WO2015121397 publication discloses the preparation of macitentan and the disclosed process is schematically represented as below.

IN 1724/MUM/2015 publication discloses a process for the preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine. The disclosed process involves esterification of 4-(bromophenyl)acetic acid with methanol in presence of sulphuric acid to provide methyl (4-bromophenyl)acetate, which on condensation with dimethyl carbonate in presence of sodium methoxide in tetrahydrofuran to provide dimethyl (4-bromophenyl)malonate, which on cyclization with formamide in presence of sodium methoxide in methanol provides 5-(4-bromophenyl)-pyrimidine-4,6-diol followed by chlorination with phosphorous oxychloride provides 5-(4-bromophenyl)-4,6-dichloropyrimidine.
IN 2431/CHE/2015 publication discloses a process for the preparation of macitentan, which involves reaction of N-[5-(4-bromophenyl)-6-chloropyrimidin-4-yl]-N′-propylsulfuric diamide with ethylene glycol in presence of tripotassium phosphate to provide N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-N′-propyl sulfuric diamide, which on condensation with 5-bromo-2-chloro pyrimidine in presence of sodium hydroxide, tetrabutylammonium bromide in methylene chloride provides macitentan.
Patent publications CN105272923A and 3334/CHE/2014 also discloses a novel process for the preparation of macitentan.
Macitentan is one of the important drugs, recently approved and available in the market for the treatment of pulmonary arterial hypertension (PAH). Hence it is advantageous to have an improved process for the preparation of macitentan, which avoids the problems allied with the reported processes.